Multidrug Treatment Research Articles

A study on the basic knowledge, attitude and practices about leprosy among the first year medical and paramedical students of a medical college in South Kerala

Leprosy is a chronic infectious disease which has a potential for deformities and is associated with social stigma and discrimination. Changing leprosy scenario has led to requirement of change in leprosy education. A cross sectional study was conducted to assess the baseline knowledge, attitude and practices about leprosy among the first year medical and paramedical students of a Medical College in South Kerala. The study included 155 students. Data was collected using a semistructured questionnaire. Eventhough there was good knowledge regarding mode of spread of the disease among students, there is stigma towards even the treated cases.86.5% said that leprosy is treatable but most of them are unaware of the free MDT of leprosy. Study concludes that there are deficiencies in knowledge and persisting stigma regarding leprosy in the study subjects. Keywords: Leprosy, Multidrug treatment, Stigma.

Pleuroparenchymal fibroelastosis in Mycobacterium avium complex pulmonary disease: clinical characteristics and prognostic impact.

The association between Mycobacterium avium complex pulmonary disease (MAC-PD) and pleuroparenchymal fibroelastosis (PPFE) has been reported previously, and interstitial pneumonia as a comorbidity is associated with a worse prognosis. However, no study has thoroughly reported on PPFE associated with MAC-PD. The present study investigated the prevalence, clinical characteristics, and prognostic impact of PPFE in patients with MAC-PD.A total of 224 patients, newly diagnosed with MAC-PD, were retrospectively reviewed. At the time of diagnosis, chest high-resolution computed tomography (HRCT), sputum examination, and clinical characteristics were collected. The extent of PPFE and MAC-PD was evaluated semi-quantitatively using HRCT scores. Risk factor analysis for clinical or radiological deterioration necessitating multidrug antimicrobial treatment within 3 years, and all-cause mortality within 5 years, from the initial diagnosis was performed based on the PPFE score.PPFE was observed in 59 out of 224 patients (26.3%). A higher PPFE score was a risk factor for dyspnoea, fatigue, and lower body mass index (BMI) (p<0.05). Although PPFE score did not correlate with clinical or radiological deterioration within 3 years (p=0.576), a higher PPFE score (adjusted OR 1.66, 95% CI 1.06–2.60, p=0.028) and lower BMI (adjusted OR 0.61, 95% CI 0.39–0.94, p=0.028) increased the risk of 5-year mortality.PPFE is a relatively common complication and an independent poor prognostic factor of MAC-PD. This study highlights the need for further studies investigating whether the presence of PPFE can be a clinical indicator for initiating treatment of MAC-PD.

New Insights into the Binding Features of F508del CFTR Potentiators: A Molecular Docking, Pharmacophore Mapping and QSAR Analysis Approach.

Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. To combat this disease, many life-prolonging therapies are required and deeply investigated, including the development of the so-called cystic fibrosis transmembrane conductance regulator (CFTR) modulators, such as correctors and potentiators. Combination therapy with the two series of drugs led to the approval of several multi-drug effective treatments, such as Orkambi, and to the recent promising evaluation of the triple-combination Elexacaftor-Tezacaftor-Ivacaftor. This scenario enlightened the effectiveness of the multi-drug approach to pave the way for the discovery of novel therapeutic agents to contrast CF. The recent X-crystallographic data about the human CFTR in complex with the well-known potentiator Ivacaftor (VX-770) opened the possibility to apply a computational study aimed to explore the key features involved in the potentiator binding. Herein, we discussed molecular docking studies performed onto the chemotypes so far discussed in the literature as CFTR potentiator, reporting the most relevant interactions responsible for their mechanism of action, involving Van der Waals interactions and π–π stacking with F236, Y304, F305 and F312, as well as H-bonding F931, Y304, S308 and R933. This kind of positioning will stabilize the effective potentiator at the CFTR channel. These data have been accompanied by pharmacophore analyses, which promoted the design of novel derivatives endowed with a main (hetero)aromatic core connected to proper substituents, featuring H-bonding moieties. A highly predictive quantitative-structure activity relationship (QSAR) model has been developed, giving a cross-validated r2 (r2cv) = 0.74, a non-cross validated r2 (r2ncv) = 0.90, root mean square error (RMSE) = 0.347, and a test set r2 (r2pred) = 0.86. On the whole, the results are expected to gain useful information to guide the further development and optimization of new CFTR potentiators.

Safety and Adherence to Venom Immunotherapy During COVID-19 Pandemic

BackgroundAccording to expert consensus, the time interval between Hymenoptera venom immunotherapy (VIT) injections can be extended up to 12 weeks, without significant impact on efficacy and safety. However, the coronavirus disease 2019 pandemic caused longer delays, and no recommendations are available to manage this huge extension.ObjectivesTo provide advice on how to resume VIT safely after a long delay from the last injection considering the potential risk factors for side effects, without starting again with the induction phase.MethodsAll the patients who delayed VIT because of the pandemic were consecutively enrolled in this single-center study. The time extension was decided according to their risk profile (eg, long prepandemic time interval, severe pre-VIT reaction, older age, multitreatments), and correlation analyses were performed to find potential risk factors of side effects.ResultsThe mean delay from the pre- (7 weeks) to the postpandemic VIT interval (15.5 weeks) was 8.5 weeks. The total amount of the prepandemic VIT maintenance dose was safely administered in 1 day in 78% of patients, whereas only 3, of 87, experienced side effects, and their potential risk factors were identified in bee venom allergy and recent VIT initiation.ConclusionsIn a real-world setting, long VIT delays may be safe and well tolerated, but more caution should be paid in resuming VIT in patients with long prepandemic maintenance interval, severe pre-VIT reaction, recent VIT initiation, older age, multidrug treatments, and bee venom allergy. This is useful in any case of long, unplanned, and unavoidable VIT delay.

A polydrug regime for treatment of sudden sensorineural hearing loss

&lt;p&gt;Sudden sensorineural hearing loss (SSNHL) is a very frightening and incapacitating event and it impairs the patient's quality of life. Steroids are considered the first line of treatment. Intratympanic dexamethasone produces a significantly higher perilymph concentration of steroids. The aim of our study was to assess the efficacy of multi-drug regimen in the management of SSNHL, to analyse the recovery and to assess use of intratympanic steroid injections (ITSI) as a primary treatment. This is a prospective study presenting as a case series of 5 cases of SSNHL. Our treatment included intratympanic steroids, oral steroids, antiplatelet drugs, rheological-agents and neuro vitamins. Complete recovery was seen in 2 (40%), partial recovery in 2 (40%), 1 patient was lost to follow up. In the patient with bilateral SSNHL, the ITSI was administered in the right ear only; which showed a significant improvement. SSNHL is described as a decline in hearing of 30 dB or more, on 3 or more frequencies over 3 days or less, with tinnitus and ear fullness. Early presentation and intervention within 72 hours is the ideal treatment. Since viral infections and vascular compromise are considered as probable theories for SSNHL, steroids, with anticoagulants, antiplatelet and rheological-agents are used as an effective therapy. Our study shows that a multi-drug treatment of SSNHL can be much more effective than a single drug treatment. We also conclude that using intratympanic steroid injections have a greater improvement as seen in the case of bilateral SSNHL.&lt;/p&gt;&lt;p&gt; &lt;/p&gt;

Current Perspectives in Meniere’s Disease Treatment: A Mini Review

Meniere’s disease (MD) is a chronic heterogeneous disorder recently found to involve multiple rare and common variants in several genes. It almost always necessitates management for a sustained period of time. Treatment options focus on improving quality of life in MD patients. Control is not always easy to achieve, requiring multidrug treatments, and even surgical procedures. Migraine, dyslipidemia, obesity, diabetes, sleep apnea, hypertension, and atherosclerosis are among the major diseases that are associated with MD and often require medical management. Migraine prophylaxis and trigger elimination, magnesium supplementation, low sodium intake, diuretics, anticoagulants, and antihypertensives are among the treatments used initially. Steroids administered orally or intratympanically are used if medical control is not beneficial. Ablation remains the definitive treatment in unilateral cases experiencing management failure, thus facilitating a customized vestibular rehabilitation protocol. Genetic study should be implemented especially when familial MD is considered. Proper gene variance targeting in MD can provide in the immediate future candidates for potential gene therapy.

Nanoscale platform for delivery of active IRINOX to combat pancreatic cancer

Due to its late diagnosis and dismal prognosis, pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating solid malignancies, with only 9% of patients surviving after being diagnosed. A multidrug chemotherapeutic regimen FOL-F-IRIN-OX (combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) offers survival benefits superior to that of gemcitabine single agent, but the treatment-related side effects are also severe. To overcome this therapeutic barrier, we developed polymeric micelles bearing active formats of irinotecan and oxaliplatin, SN38 and 1,2-diaminocyclohexane‑platinum (II), DACHPt. Crosslinked micelles were prepared using amphiphilic PEG-b-poly(L-glutamic acid)/SN38 conjugates and subsequently loaded with DACHPt. The dual drug-loaded micelles exhibited improved colloidal stability, prolonged drug release and remarkable cytotoxicity in human pancreatic cancer cell lines and KrasG12D; Trp52R172H/+; Pdx-1 Cre murine tumor organoids models. In vivo, (SN38 + DACHPt)-loaded micelles displayed superior antitumor and antimetastatic activities without impairing safety. Our results suggest that nanomedicine mimicking irinotecan and oxaliplatin as parts of FOLFIRINOX regimen may further improve the feasibility of this multidrug treatment for patients with advanced pancreatic cancer.

Abstract PO-028: Could pharmacodynamic modelling of FOLFIRINOX lead to more therapeutically advantageous treatment of pancreatic cancer?

Abstract Pancreatic cancer is one of the most fatal human cancers with a 5-year survival rate of approximately 6%. Pancreatic Ductal Adenocarcinoma (PDAC) is the predominant (~90%) histological type among pancreatic cancers. The poor prognosis of PDAC is due to a combination of factors including late stage diagnosis at a locally advanced or metastatic stage, due to its asymptomatic progression. PDAC is a highly chemoresistant malignancy owing to its genetic heterogeneity and dense stromal environment. FOLFIRINOX (FFX) is a combinatorial chemotherapeutic approach consisting of 5-Fluorouracil (5-FU)/Leucovorin (LV), Irinotecan and Oxaliplatin, and is a first-line treatment option for pancreatic cancer patients. Despite its superior clinical benefit for the treatment of metastatic PDAC compared to gemcitabine, its high toxicity profile limits its use to patients with high performance status. In-depth pharmacodynamic (PD) modelling of the interactions between the individual agents of the regimen is required. Here, the effect of the FFX regime was investigated using both established and primary pancreatic cancer cell-lines cultured as 2D and 3D models. Cells were exposed to a concentration range of each agent in single, double and triple combinations. Cell viability assayed after 5 days. The addition of LV to 5-FU had no effect in vitro in Panc-1, Mia-PaCa-2 and primary PT99 cells, and was excluded from further analysis. The active metabolite of Irinotecan, SN-38, was used in-vitro. The Bliss Independent method was used to fit the cell viability data for all cell lines using SAS 9.4 software. A psi value less than 1 suggests synergistic interactions. Of 4 cell lines tested, MIA-PaCa-2 cells were the most sensitive to the agents of the FFX regimen, with the triple combination demonstrating synergistic interactions with a psi value of 0.036. However, in Panc-1, BxPC-3 and PT127 cells the triple combination was antagonistic, with psi values of 5.167, 3.598 and 5.349 respectively. For the double combination, Ox + SN-38 was shown to have synergistic interactions in 3 of 4 cell lines. The 5-FU + SN-38 and 5-FU + Ox combinations were synergistic in 3 of 4 cell lines. The differences in cellular response observed between the cell lines mirrors the heterogeneity of patients in the clinic and highlights the importance of mathematical modelling to better understand the PD interactions of multidrug treatment regimens. While the triple combinations were determined as antagonistic, meaning the net effect is less than the additive effect of individual agents, it still resulted in greater cell kill than any agent alone. Therefore despite findings of antagonism this further supports the need for all 3 drugs. In conclusion, the results suggest a complex interplay between the three agents, and the PD data could be used to assess whether lower doses and/or alternate dosing schedules would be feasible. This potentially translatable finding may result in FFX being available to more PDAC patients. Citation Format: Taylor Allen-Coyle, Jin Niu, Eva Welsch, Fiona O'Neill, Martin Clynes, Finbarr O'Sullivan, Donald E. Mager, Robert M. Straubinger, Sandra Roche. Could pharmacodynamic modelling of FOLFIRINOX lead to more therapeutically advantageous treatment of pancreatic cancer? [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-028.

Survival status and its predictors among multi-drug resistance tuberculosis treated patients in Ethiopia: Multicenter observational study.

Although substantial progress has been made in combating the crisis of multi-drug resistance tuberculosis (MDR-TB), it remained the major public health threat globally. To assess patients' survival and its predictors among patients receiving multi-drug resistance tuberculosis treatment at MDR-TB treatment centers of southern and southwestern Ethiopia. A multicenter retrospective observational study was conducted from April 14 to May 14, 2019, among patients receiving MDR-TB treatment at three MDR-TB treatment centers, Butajira, Arbaminch and Shenengibe Hospitals, located in south and southwestern Ethiopia. A total of 200 records were reviewed using a check list adopted from the national MDR-TB treatment charts and other relevant documents. Data were entered into Epi-Data version 4.2.0 for cleaning and exported to STATA-13 for analysis. Descriptive analysis was carried out and results were presented by text, tables, and charts. Kaplan-Meier (log-rank test) and Cox regression were used to compare baseline survival experience and to determine predictors of patients' survival (death), respectively. The adjusted hazard ratio (AHR) was used to measure the strength of association and a p-value of <0.05 was considered to declare statistical significance. Of 200 patients, 108 (54%) of them were males. The mean (+ standard deviation) age of the study population was 32.9±9.5years. During follow-up, 22 (11%) deaths were reported. The overall incidence density of death was 11.99, 95% CI [7.89-18.21] per 100,000person-years. The median (interquartile range (IQR)) survival time was 375(249-457) days. Comorbidity (AHR = 23.68, 95% CI [4.85-115.46]), alcohol consumption (AHR = 4.53, 95% CI [1.21-16.97]), and history of poor adherence (AHR = 12.27, 95% CI [2.83-53.21]) were independently associated with patients' survival (death). In this study, the incidence density of mortality was very high. Alcohol consumption, poor adherence, and the presence of comorbidity were independently associated with death. Hence, alcohol users, patients with comorbidity and poor adherence should be given due attention during therapy.

Novel SARS-CoV-2 and COVID-2019 Outbreak: Current Perspectives on Plant-Based Antiviral Agents and Complementary Therapy

Abstract: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused the novel Corona Virus Disease 2019 (COVID-19), which has been defined as a pandemic by the World Health Organization (WHO) in 2020. The rapid global spread of SARS-CoV-2 virus as a global health emergency has emphasized to findeffective treatment strategies in clinical trials. The several drug trials including Lopinavir (LPV) and Ritonavir, Chloroquine (CLQ), Hydroxychloroquine, Favipiravir (FPV), Remdevisir (RDV), Nitazoxanide, Ivermectin and Interferon, have been explored in COVID-19 patients and some of the drugs have been waiting clinical approval for their anti-SARS-CoV-2 activities. Clinical trials are still ongoing to discover promising new multidrug combination treatment for COVID-19 patients. Considering the difficulties to ascertain efficient drug candidates and the lack of specific anti-viral therapies against COVID-19 outbreak, the current management of SARS-CoV-2 should mainly be supportive. From this point of view, enhancing the immune system through medicinal plants with wide range of bioactive compounds, which exhibit antiviral activities, can play significant roles to increase defense barrier in COVID-19 patients. On the other hand, plant-based agents as complementary and alternative therapies have potential advantages to reduce symptoms of this life-threatening disease and could promote the public health. Recently, there has been a remarkable progress in the field of antiviral herbal therapy owing to increasing concerns about the development of drug resistance and limited advances in the field of antiviral drug discovery. This review provides an overview of published information onbiology, genomic structure, replication cycle and pathogenesis of SARS-CoV-2. It also aims to assemble the fact and a scientific intellectual groundwork on development of antiviral herbal therapy on the bases of extensive literature collection. Key words: SARS-CoV-2, COVID-19, Outbreak, Medicinal plants, Antiviral.

Clinical profile of children with epilepsy: a cross-sectional study

Introduction: One of the most common chronic neurological disorders is epilepsy, affecting as many as 45 million individuals worldwide. The occurrence is higher in children below the age of three. Around 60 percent to 70 percent of epilepsy patients have an effective response to treatment with antiepileptic medications. This cross-sectional study aimed to explore the clinical profile of children with epilepsy.Methods: Total of 100 children with different types of epilepsy was included in this study. After getting informed consent from the parents, all the demographic data, family history, clinical and laboratory investigations were recorded, and the results were statistically analyzed and discussed.Results: 69 patients had tonic-clonic seizures, 15 patients had a complete partial seizure, 7 patients had absence seizures, 4 patients had unclassified seizures, 3 patients had simple partial seizures, 1 patient had myoclonic seizures, atonic seizures and multiple seizures. Aetiology, 72 patients had an idiopathic cause, 10 patients had hypoxic ischemia, 8 patients had Central nervous system (CNS) infection, 4 patients had cerebral palsy and space-occupying lesion, 2 patients had trauma. Comorbidity, 84 patients had none, 4 patients had mental retardation, 3 patients had eye diseases, cerebral palsy, protein-energy malnutrition, mental retardation with cerebral palsy, 1 patient had a hearing impairment. Drug therapy, 63 patients had sodium valproate, 11 patients had carbamazepine, 2 patients had multidrug treatment, and 1 patient had sodium phenytoin.Conclusion: A significant amount of the aetiology of the condition is expressed among preventable causes of epilepsy. For generalized tonic clonic seizure, sodium valproate was observed to have more positive effects in paediatric patients.

Two Sites - One Major Problem

The authors present the case of a 36-year-old woman with disseminated tuberculosis shown by pulmonary nodules and urogenital involvement. Positive cultures for Mycobacterium tuberculosis in urine and bronchial secretions made the diagnosis. After three months of multidrug treatment, there was a clinical and radiologic improvement. This case highlights an uncommon case of an immunocompetent patient with disseminated tuberculosis. A delay in the diagnosis of pulmonary tuberculosis can result in serious public health problems with disease spread.

Essential Oils from Vitex agnus castus L. Leaves Induces Caspase-Dependent Apoptosis of Human Multidrug-Resistant Lung Carcinoma Cells through Intrinsic and Extrinsic Pathways

Essential oil (EO) fractions of plants are complex mixtures of volatile compounds with broad-spectrum biological properties. In the current study, the EO content of Vitex agnus castus L. (VAC) leaves growing in the Aegean region of Turkey was extracted and identified. Then, VAC EOs were investigated for their potential antioxidant, cytotoxic and apoptotic effects in human H69AR multi-drug resistant cancer cells. EOs were isolated by hydrodistillation and chemical composition was determined by GC-MS. Cell viability was assessed via MTT and trypan blue assays. Antioxidant activity was evaluated by measuring the total antioxidant activity and free radical scavenging activity. Apoptosis was evaluated via DNA fragmentation and caspase 3/7 activity assays. Changes in the levels of apoptotic genes were determined by RT-qPCR. The results indicated strong antioxidant activity and cytotoxic effect on H69AR cancer cells but not on HEK-293 human normal cells indicating the tumor-specific effect. VAC EOs induced caspase 3/7 activation and apoptosis through triggering both extrinsic- and intrinsic-pathways by modulating Bcl-2, Bcl-XL, Bax, Bad, FADD, Caspase-8, Caspase-9, TRAIL R1/DR4 and TRAIL R2/DR5. This study revealed that VAC EOs may be a promising candidate in the development of novel therapeutic agents for multi-drug resistant lung cancer treatment.

Self-assembled peptide nanoparticles with endosome escaping permits for co-drug delivery

The diagnosis and treatment of major diseases, especially tumors, was the key to improving the cure rate and survival rate of patients. Therefore, one of the main goals of modern medicine was to develop effective, non-toxic treatments. This paper successfully established dipeptide nanoparticles/clofarabine/aptamer AS1411/influenza hemagglutinin peptide/siRNA/doxorubicin (DNPs/Clolar/AS1411/HA/RNA/DOX) multi-functional nanoparticles for specific delivery, cancer treatment and bioimaging. It was an ideal choice for multi-drug synergy treatment. First, non-toxic DNPs formed by self-assembly of dipeptides with safe and biocompatible effect. Second, from the perspective of the multi-functional nanoparticles for nano-drug tumors imaging monitoring, AS1411 and HA were used as cell permits for enhancing the specificity of cell drug delivery ability and improving the endosomal escape, respectively. Third, the multi-functional nanoparticles with Clolar, siRNA and DOX, three drug synergistic treatments were used to improve the therapeutic effect of tumors. Both cell experiments and vivo experiments demonstrated that the synergistic treatment of the multi-drugs was superior to the effect of single-drug therapy. Thus, the proposed multi-functional nanoparticles have initiated new ideas for these hybrid anticancer drugs based on peptide self-assembled nanocarriers and its widely applications in biomedicine.

Improving the Treatment of Acute Lymphoblastic Leukemia.

l-Asparaginase (EC 3.5.1.1) was first used as a component of combination drug therapies to treat acute lymphoblastic leukemia (ALL), a cancer of the blood and bone marrow, almost 50 years ago. Administering this enzyme to reduce asparagine levels in the blood is a cornerstone of modern clinical protocols for ALL; indeed, this remains the only successful example of a therapy targeted against a specific metabolic weakness in any form of cancer. Three problems, however, constrain the clinical use of l-asparaginase. First, a type II bacterial variant of l-asparaginase is administered to patients, the majority of whom are children, which produces an immune response thereby limiting the time over which the enzyme can be tolerated. Second, l-asparaginase is subject to proteolytic degradation in the blood. Third, toxic side effects are observed, which may be correlated with the l-glutaminase activity of the enzyme. This Perspective will outline how asparagine depletion negatively impacts the growth of leukemic blasts, discuss the structure and mechanism of l-asparaginase, and briefly describe the clinical use of chemically modified forms of clinically useful l-asparaginases, such as Asparlas, which was recently given FDA approval for use in children (babies to young adults) as part of multidrug treatments for ALL. Finally, we review ongoing efforts to engineer l-asparaginase variants with improved therapeutic properties and briefly detail emerging, alternate strategies for the treatment of forms of ALL that are resistant to asparagine depletion.

Host-Pathogen Interaction as a Novel Target for Host-Directed Therapies in Tuberculosis.

Tuberculosis (TB) has been a transmittable human disease for many thousands of years, and M. tuberculosis is again the number one cause of death worldwide due to a single infectious agent. The intense 6- to 10-month process of multi-drug treatment, combined with the adverse side effects that can run the spectrum from gastrointestinal disturbances to liver toxicity or peripheral neuropathy are major obstacles to patient compliance and therapy completion. The consequent increase in multidrug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB) cases requires that we increase our arsenal of effective drugs, particularly novel therapeutic approaches. Over the millennia, host and pathogen have evolved mechanisms and relationships that greatly influence the outcome of infection. Understanding these evolutionary interactions and their impact on bacterial clearance or host pathology will lead the way toward rational development of new therapeutics that favor enhancing a host protective response. These host-directed therapies have recently demonstrated promising results against M. tuberculosis, adding to the effectiveness of currently available anti-mycobacterial drugs that directly kill the organism or slow mycobacterial replication. Here we review the host-pathogen interactions during M. tuberculosis infection, describe how M. tuberculosis bacilli modulate and evade the host immune system, and discuss the currently available host-directed therapies that target these bacterial factors. Rather than provide an exhaustive description of M. tuberculosis virulence factors, which falls outside the scope of this review, we will instead focus on the host-pathogen interactions that lead to increased bacterial growth or host immune evasion, and that can be modulated by existing host-directed therapies.

Disability progression among leprosy patients released from treatment: a survival analysis

BackgroundLeprosy can be cured, but physical disability (PD) as a result of the infection can progress in the post-release from treatment phase. This study evaluated the likelihood of, and factors associated with, the progression of the PD grade post-release from treatment among leprosy patients treated in Cáceres-MT, Brazil in the period 2000 to 2017.MethodsA retrospective cohort study and survival analysis were performed in the hyperendemic municipality of Cáceres in the state of Mato Grosso. The study population consisted of newly diagnosed leprosy patients released from treatment between January 1, 2000 and December 31, 2017. The main outcome was the progression of the PD grade with regard to probability and time; and the evaluated covariates included clinical, operational and demographic variables. The Cox proportional risk model was used to estimate the risk ratio (Hazard Ratios) of the covariates. Both an univariate and a multivariate analysis were implemented, with 95% confidence intervals.ResultsThe mean time for progression of the PD grade was 162 months for PB and 151 months for MB leprosy patients. The survival curve showed that 15 years after the release from treatment, the probability of PD grade progression was 35%, with no difference between PB and MB or age groups. Leprosy reactions and registered medical complaints of any kind during treatment were identified as risk factors with Hazard Ratios of 1.6 and 1.8 respectively.ConclusionsPeople released from treatment as cured of leprosy are susceptible to worsening of the PD, especially those who have had complications during multi-drug therapy treatment. This indicates that leprosy patients should be periodically monitored, even after the successful completion of multidrug therapy.

COMBSecretomics: A pragmatic methodological framework for higher-order drug combination analysis using secretomics

Multi drug treatments are increasingly used in the clinic to combat complex and co-occurring diseases. However, most drug combination discovery efforts today are mainly focused on anticancer therapy and rarely examine the potential of using more than two drugs simultaneously. Moreover, there is currently no reported methodology for performing second- and higher-order drug combination analysis of secretomic patterns, meaning protein concentration profiles released by the cells. Here, we introduce COMBSecretomics (https://github.com/EffieChantzi/COMBSecretomics.git), the first pragmatic methodological framework designed to search exhaustively for second- and higher-order mixtures of candidate treatments that can modify, or even reverse malfunctioning secretomic patterns of human cells. This framework comes with two novel model-free combination analysis methods; a tailor-made generalization of the highest single agent principle and a data mining approach based on top-down hierarchical clustering. Quality control procedures to eliminate outliers and non-parametric statistics to quantify uncertainty in the results obtained are also included. COMBSecretomics is based on a standardized reproducible format and could be employed with any experimental platform that provides the required protein release data. Its practical use and functionality are demonstrated by means of a proof-of-principle pharmacological study related to cartilage degradation. COMBSecretomics is the first methodological framework reported to enable secretome-related second- and higher-order drug combination analysis. It could be used in drug discovery and development projects, clinical practice, as well as basic biological understanding of the largely unexplored changes in cell-cell communication that occurs due to disease and/or associated pharmacological treatment conditions.

The impact of coronavirus infectious disease 19 (COVID-19) on oral health.

Health services across the world face an unprecedented situation as a result of a global COVID‐19 outbreak. Urgent joined research efforts regarding the SARS‐COV‐2 rapid tests, accurate diagnosis, especially early recognition, and effective treatment of life‐threatening complications would be highly desirable for humanity and medical workforce all over the world that try to combat a current global pandemic threat. Due to indirect complex effect, intensified COVID‐19 therapies and multi‐drug treatment, it is believed that some oral conditions could be aggravated by COVID‐19 disease, particularly those with autoimmune aetiology, linked to compromised immune system or long‐term pharmacotherapy.

Long-Term Treatment Outcome of Progressive Mycobacterium Avium Complex Pulmonary Disease.

Background: Multidrug therapy is essential for preventing respiratory failure in patients with highly progressive Mycobacterium avium complex pulmonary disease (MAC-PD). However, the prognosis and long-term outcome following combination therapy is poorly understood. Methods: We retrospectively evaluated the clinical characteristics and long-term outcomes in patients with chemo-naïve progressive MAC-PD, hospitalized for first-line multidrug therapy. Results: Among 125 patients, 86 (68.8%) received standardized treatment (rifampicin, ethambutol, clarithromycin), 25 (20.0%) received a fluoroquinolone (FQ)-containing regimen, and 53 (42.4%) received aminoglycoside injection. The sputum conversion rate was 80.0%, and was independently associated with standardized treatment. The incidence of refractory disease (45.6%) was independently and negatively associated with standardized regimen and aminoglycoside use. Choice of an FQ-containing regimen was not associated with positive outcome. Clarithromycin resistance occurred in 16.8% and was independently associated with refractory disease. MAC-PD-associated death occurred in 3.3% of patients with non-cavitary nodular bronchiectasis (NB) and 21.3% with cavitary MAC-PD over a median follow-up period of 56.4 months. The rates of MAC-PD-associated death were comparable between cavitary-NB and fibrocavitary disease. Concurrent chronic pulmonary aspergillosis (CPA) occurred in 13 (17.3%) patients with cavitary MAC-PD, and age, diabetes mellitus, and CPA were independent risk factors for mortality. Conclusions: Standardized intensive multidrug treatment reduces disease progression and persistence in progressive MAC-PD. Cavitary NB may differ from, rather than being just an advanced stage of, non-cavitary NB. The high incidence and significant mortality of CPA in cavitary MAC-PD highlight the need for early diagnosis and treatment.